Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects

Ritobrata Ghose, Fabio Pezzano, Rémi Badia, Savvas Kourtis, Ilir Sheraj, Shubhamay Das, Antoni Gañez Zapater, Upamanyu Ghose, Sara Musa-Afaneh, Lorena Espinar, Albert Coll-Manzano, Katja Parapatics, Saška Ivanova, Paula Sànchez-Fernàndez- de-Landa, Dragana Radivojevikj, Valeria Venturini, Stefan Wieser, Antonio Zorzano, André C. Müller, Verena Ruprecht () and Sara Sdelci ()
Additional contact information
Ritobrata Ghose: The Barcelona Institute of Science and Technology
Fabio Pezzano: The Barcelona Institute of Science and Technology
Rémi Badia: The Barcelona Institute of Science and Technology
Savvas Kourtis: The Barcelona Institute of Science and Technology
Ilir Sheraj: The Barcelona Institute of Science and Technology
Shubhamay Das: The Barcelona Institute of Science and Technology
Antoni Gañez Zapater: The Barcelona Institute of Science and Technology
Upamanyu Ghose: University of Oxford
Sara Musa-Afaneh: The Barcelona Institute of Science and Technology
Lorena Espinar: The Barcelona Institute of Science and Technology
Albert Coll-Manzano: The Barcelona Institute of Science and Technology
Katja Parapatics: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Saška Ivanova: The Barcelona Institute of Science and Technology
Paula Sànchez-Fernàndez- de-Landa: The Barcelona Institute of Science and Technology
Dragana Radivojevikj: The Barcelona Institute of Science and Technology
Valeria Venturini: The Barcelona Institute of Science and Technology
Stefan Wieser: University of Innsbruck
Antonio Zorzano: The Barcelona Institute of Science and Technology
André C. Müller: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Verena Ruprecht: The Barcelona Institute of Science and Technology
Sara Sdelci: The Barcelona Institute of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract The physical tissue microenvironment regulates cell state and behaviour. How mechanical confinement rewires the subcellular localisation of organelles and affects cellular metabolism is largely unknown. In this study, proteomics analysis revealed that cellular confinement induced a strong enrichment of mitochondrial proteins in the nuclear fraction. Quantitative live cell microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery in vitro, reflecting a physiologically relevant phenomenon in patient-derived tumours. This nucleus-mitochondria proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the nucleus-mitochondria proximity results in a nuclear ATP surge, which can be regulated by the genetic and pharmacological modulation of mitochondrial ATP production or via alterations of the actin cytoskeleton. The confinement-induced nuclear ATP surge has physiologically significant long-term effects on cell fitness, driven by changes in chromatin state, enhanced DNA damage repair, and cell cycle progression during mechanical cell deformation. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell proliferation under mechanical confinement stress by facilitating chromatin state transitions.

Date: 2025
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DOI: 10.1038/s41467-025-61787-x

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